Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model

Rodenbeck, Stacey D.; Zarse, Chad A.; McKenney‐Drake, Mikaela L.; Bruning, Rebecca S.; Sturek, Michael; Chen, Neal X.; Moe, Sharon M.

doi:10.1093/ndt/gfw274

Cited by 17 publications

(23 citation statements)

References 85 publications

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“…With these derangements there was no difference in resting [Ca 2+ ] i . However, SERCA activity NCX1 expression were lower in the CKD+Ca animals compared to CKD without calcium[47]. Based on these findings, one would have expected the baseline [Ca 2+ ] i to be greater in CKD+Ca animals than in the CKD animals, but we did not observe that.…”

Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 69%

“…In animal models, altered [Ca 2+ ] i homeostasis has been found in atherosclerosis [44] and arteriosclerosis[45]. We recently demonstrated decreased expression of myocardin in ex vivo arterial tissue and cultured VSMC from CKD animals compared to normal littermates [46] and an increase in resting [Ca 2+ ] i in freshly isolated VSMC in CKD compared to normal animal[47]. …”

Section: Calcium and Vascular Smooth Muscle Phenotypementioning

confidence: 99%

“…Using freshly isolated VSMC from our CKD rats, we tested the hypothesis that there is increased [Ca 2+ ] i in VSMC with progressive loss of kidney function [47]. In this study, we freshly isolated aorta VSMC to better evaluate the in vivo state, as cultured cells immediately take on a proliferative phenotype[48].…”

Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 99%

“…In this study, we freshly isolated aorta VSMC to better evaluate the in vivo state, as cultured cells immediately take on a proliferative phenotype[48]. Our results demonstrated that compared to normal animals, resting [Ca 2+ ] i levels were lower in early CKD, but were elevated in advanced CKD indicating that progressive uremia leads to a rise in VSMC [Ca 2+ ] i [47]. This increase in resting [Ca 2+ ]I was due, at least in part, to altered SERC2a function and impaired extrusion of calcium and decreased Na + /Ca 2+ exchanger-1 (NCX1) expression.…”

Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 99%

“…TRPC1 = transient receptor potential canonical 1 channel; NCX = Na+/Ca2+ exchanger; Cai = intracellular free Ca2+; IP3R = inositol 1,4,5-trisphosphate receptor; SERCA = sarco/endoplasmic reticulum Ca2+ ATPase; RyR = ryanodine receptor; SR = sarcoplasmic reticulum; CaSR = SR Ca2+. (From [47])…”

Section: Figurementioning

confidence: 99%

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Calcium as a cardiovascular toxin in CKD-MBD

Moe

2017

Bone

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Disordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD.

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Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 69%

Section: Calcium and Vascular Smooth Muscle Phenotypementioning

confidence: 99%

Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 99%

Section: Calcium Signaling and Vascular Smooth Muscle Cell Phenotypementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Calcium as a cardiovascular toxin in CKD-MBD

Moe

2017

Bone

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Non‐Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD)

et al. 2022

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Chronic kidney disease‐mineral and bone disorder (CKD‐MBD) increases cardiovascular calcification and skeletal fragility in part by increasing systemic oxidative stress and disrupting mineral homeostasis through secondary hyperparathyroidism. We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before end‐stage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKD‐MBD, the Cy/+ rat, beginning early in CKD with the NADPH oxidase (NOX1/4) inhibitor GKT‐137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KP‐2326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased C‐terminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8‐OHdG in the serum or aorta. KP treatment reduced aortic 8‐OHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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BMP9/COX‐2 axial mediates high phosphate‐induced calcification in vascular smooth muscle cells via Wnt/β‐catenin pathway

Wang

Ren

et al. 2017

J of Cellular Biochemistry

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Vascular calcification is a notable risk factor for cardiovascular system. High phosphate can induce calcification in vascular smooth muscle cells (VSMCs), but the detail mechanism underlying this process remains unclear. In the present study, we determined the relationship between high phosphate and bone morphogenetic protein 9 (BMP9) in VSMCs, the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs, as well as the possible mechanism underlying this biological process. We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs. Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin (α-SMA) apparently, but increases the level of Runx-2, Dlx-5, and ALP in VSMCs. Meanwhile, BMP9 increases the level of OPN and OCN, promotes mineralization in VSMCs and induces calcification in thoracic aorta. High phosphate and over-expression of BMP9 increases the level of COX-2. Over-expression of COX-2 enhances the inhibitory effect of BMP9 on α-SAM and increases the level of OPN and OCN induced by BMP9. However, inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta. For mechanism, we found that high phosphate or BMP9 increases the level of β-catenin and p-GSK3β in VSMCs, but no substantial effect on GSK3β. However, COX-2 inhibitor decreases the expression of β-catenin induced by BMP9. Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/β-catenin pathway.

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Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model

Abstract: With progressive CKD in the Cy/+ rat there is increased resting [Ca 2+ ] i in VSMCs due, in part, to increased SOCE and impaired calcium extrusion from the cell. Such changes may predispose VSMCs to phenotypic changes that are a prerequisite to calcification.

Cited by 17 publications

References 85 publications

Calcium as a cardiovascular toxin in CKD-MBD

Calcium as a cardiovascular toxin in CKD-MBD

Non‐Additive Effects of Combined NOX1/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD)

BMP9/COX‐2 axial mediates high phosphate‐induced calcification in vascular smooth muscle cells via Wnt/β‐catenin pathway

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